Ernest h



Patented Apr. 11, 1939 UNITED STATES PATENT OFFICE THIOBARBITURIC ACID DERIVATIVES Ernest H. Volwiler, Highland Park, and Donalee L. Tabern, Lake Bluff, Ill., assignors to Abbott Laboratories, North Chicago, 111., a. corporation of Illinois No Drawing. Application August 17, 1936, Serial No. 96,478

6 Claims.

R (JO-NH t :3 R XntH in which R is selected from the group consisting 10 of cyclic and cyclic substituted alkyl groups, R is selected from the group consisting of hydrogen, saturated and unsaturated alkyl groups, and cyclic substituted alkyl groups, and X is a member of the group consisting of =0 and =NH.

In the co-pending application above referred to and in the co-pending divisional application, Serial No. 68,638, filed March 13, 1936, we have pointed out that certain higher alkyl thicbarbituric acids and their salts, particularly those containing secondary alkyl groups, possess unusual properties, being intense and rapid but brief of action. Theyare of value as hypnotics for production of brief periods of sleep, and of even greater importance as intravenous surgical anesthetics.

We have discovered that the same properties are resident in certain cyclic (aryl) and cyclic substituted alkyl (aralkyl) thiobarbiturates. A thiobarbiturate to be efficacious should, of course,

have a favorable comparative ratio between potency and toxicity.

Our compounds may be synthesized (l) by condensation of the requisite malonic esters with thiourea or (2) by condensation of the cyanoacetic esters with thiourea followed by acid hydrolysis and purification. The following specific examples employing both methods of preparation will serve to illustrate our invention.

4o EXAMPLE I Cyclohexyl, ethyl thiobarbituric acid yl thiobarbituric acid melts at 205-0'7 C. and has the following formula:

CaHn C0-NH o o=s aH/ -11111 EXAMPLE II Phenyl, ethyl thiobarbiturz'c acid 05115 CONH A 1 =S 02m (Jo-1 m EXAMPLE III cyclohearenyl, ethyl thz'obarbiturz'c acid 88 grams of cyclohexanone, 99 grams of cyanoacetic methyl ester and 10 c. c. of piperidine are heated at 100 C. for about three hours and then diluted and extracted with water and benzene. 25 The ester boils at 165 C. at 20 mm. pressure.

73 grams of the above cyclohexenyl cyanoacetic methyl ester is next added to a solution of 9.2 grams of sodium in absolute alcohol followed by the addition. of one mole of ethyl bromide. A 30 spontaneous reaction takes place. After refluxing the mixture for a short period of time, the ester is isolated in the usual manner. This compound boils at -45 C. at 2 mm. pressure.

43 grams of the above cyclohexenyl, ethyl cy- 35 anoacetic methyl ester is then condensed with 25 grams of thiourea in presence of an absolute a1- cohol solution of sodium ethylate prepared from 14. grams of sodium. The imino thiobarbituric acid formed melts at 215-220 C. and has the 40 following formula:

This compound may be readily hydrolyzed by boiling with 5 to 10 percent sulphuric acid 50- 50 lution to give cyclohexenyl, ethyl thiobarbituric acid having a melting point of 186-188 C. and having the following formula:

EXAMPLE IV Cyclohexenyl, allyl thiobarbituric acid This compound is prepared in the manner described in Example III. The cyclohexenyl, allyl thiobarbituric acid melts at 148-150 C. and has the following formula:

Exam ne V Cyclopentyl, ethyl thiobarbzturic acid This compound may be obtained by reacting monethyl malonic ester with one mole of sodium ethylate containing one mole of cyclopentyl bromide. The resultant cyclopentyl, ethyl malonic ester boils at 170 C. at mm. pressure. This compound is then condensed with thiourea in presence of sodium ethylate in the usual manner and a good yield of cyclopentyl, ethyl thiobarbituric acid melding at 172-173 C. is obtained. This compound has the following formula:

The following cyclic thiobarbituricacids have been prepared:

Table Melting Compound point Degrees I Phenyl, ethyl.-- 216-17 Phenyl. allyl-.- 210 Mono benzyl 220 Dibenzyl 205-8 Benzyl, allyl 149-50 Oyclopentyl, et yl 172-3 Oyclohexyl, ethyl 205-7 Gyclohexenyl, ethyl 186-8 3-methyl cyclohexenyl, ethy1. 150-55 Oyclohexenyl, isopropyll85 7 Cyclohexenyl, allyl 148-50 The cyclic thiobarbituric acid compounds react with various basic substances such as alkali and alkaline earth hydroxides, amines, etc. to form soluble salts. Solid salts may be secured by evaporation of aqueous or alcoholic solutions of the salts or by precipitation with suitable media such as ether, benzene, petroleum ether,

in which R is selected from the group consisting of saturated and unsaturated alkyl groups and R. represents a cycloaliphatic group.

2. Anesthetic and hypnotic compounds having the formula:

CzHn (IO-NH in which R represents a cycloaliphatic group.

3. Cyclohexyl, ethyl thio-barbituric acid having the following formula:

CoHn CONH C2115 (JO-NH 4. Cyclohexyl, ethyl thiobarbituric acid having the following formula 06H (|JO-NH o o=s 05H; A30-NH 5. Cyclopentyl, ethyl thiobarbituric acid having the following formula 06m (JO-NH 5 0:8 Unfit 3 OII\TH 6. A thio-barbituric acid having the formula:

at least five carbon atoms, and R is a lower alkyl group having at least two carbon atoms.

ERNEST H. VOLWILER. DONALEE L. TABERN.

CERTIFICATE OF- CORRECTION.

Patent No. 2,155,75 April 11, 95%

I ERNEST H. voLwnER, ET AL. 7

It 'is'her-eby certified that eri'onappears inthef printed specification" of the above numbered patent re quiring correction as follbws: Page 2, second lqmn, line 55, claim for "Cyclohexyl? read Cyclohexenyl; and that the same may conform to-th e fepord ofthe case in the Patent Offic.

Signed and sealed this'50th"day of May. A. .D. 1959 Henry Van Arsd ale '(Sea1) Acting Commissioner qf Patents.

said. Letters Patent shouldb e read with this correction 'thpere-in that the 

